Candidiasis represents now the fourth most frequent nosocomial infection in the US and worldwide and C. albicans remains the most frequent causative agent of candidiasis. Unfortunately these infections are associated with unacceptably high morbidity and mortality rates. A variety of manifestations of candidiasis are associated with biofilm formation on the surface of different types of surfaces. Biofilm formation carries important consequences since sessile cells in biofilms display phenotypic traits that are dramatically different from their planktonic counterparts, such as increased resistance to antifungal agents and protection from host defenses. Once established, biofilms have the potential to initiate or prolong infections by providing a safe reservoir from which organisms can invade local tissue, seed new infection sites, or resist eradication efforts. The net effect is that Candida biofilms adversely impact the health of these patients, with increasing frequency and severity, and with soaring economic sequelae. Therefore, the main objective of the proposed studies is to devise novel strategies to prevent C. albicans biofilm formation. To this end we will: i) use a phenotype-based approach based on the high throughput screening for small molecule compounds which inhibit C. albicans biofilm formation, and ii) characterize the biofilm-inhibitory effects of selected bioactive molecules identified as "hits" and "leads" during the initial screens. These assays take advantage of a simple, rapid, robust, accurate and highly reproducible microtiter-based model for the formation of Candida biofilms developed in this laboratory that is ideally suited for automation and high throughput applications. Small-molecule-based approaches provide powerful means to address experimentally challenging and complex biological phenomena, such as biofilm formation, while simultaneously identifying new potential targets for drug development. to public health: Biofilm formation has severe consequences for human health. The main idea behind this study is that by eliminating the ability of C. albicans to form biofilms, a substantial reduction in morbidity, mortality and extended hospital stay can be achieved while simultaneously reducing healthcare costs. [unreadable] [unreadable] [unreadable]